The present invention relates to the use of alpha-1-antitrypsin (AAT) for the preparation of compositions for the treatment of chronic wounds.
alpha-1-antitrypsin (AAT), also known as alpha-1-proteinase inhibitor or serpin, is a mammalian polypeptide having a molecular weight of approximately 54 kDa. It is a potent fluid phase inhibitor of serine proteases, and forms a tightly bound, stoichiomedric complex with elastase. It can be inactivated by cleavage within its reactive centre. For example, neutrophil collagenase (MMP8) is know to degrade and inactivate AAT.
AAT deficiency is a congenital disorder that is principally associated with liver disease in children and emphysema in young adulthood. It is thought that AAT deficiency results in loss of protection in the lung against neutrophil elastase, resulting in breakdown of the architecture of the lung. AAT has been administered in intravenous and aerosol formats for the treatment of pulmonary emphysema.
It is an object of the present invention to provide improved compositions for the treatment of chronic wounds, such as decubitis ulcers, pressure sores and venous ulcers.
The present invention provides the use of alpha-1-antitrypsin for the preparation of a composition for the treatment of a chronic wound.
Preferably, the composition is a wound dressing composition. That to say, the composition is preferably a liquid, semi-solid or solid composition for application directly to the surface of a wound, or the composition is applied to the surface of, or incorporated into, a solid wound contacting layer such as a wound dressing gauze or film. More preferably, the wound dressing composition is a fluid or a gel comprising from 100 ng to 10 mg/ml, preferably 10 xcexcg to 1 mg/ml of AAT in combination with conventional pharmaceutical excipients for topical application to a wound. Suitable carriers include: Hydrogels containing cellulose derivatives, including hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose and mixtures thereof; and hydrogels containing polyacrylic acid (Carbopols). Suitable carriers also include creams/ointments used for topical pharmaceutical preparations, e.g. creams based on cetomacrogol emulsifying ointment. The above carriers may include alginate (as a thickener or stimulant), preservatives such as benzyl alcohol, buffers to control pH such as disodium hydrogen phosphate/sodium dihydrogen phosphate, agents to adjust osmolarity such as sodium chloride, and stabilisers such as EDTA.
Alternatively, the wound dressing composition may be a slow release solid composition, in which the AAT is dispersed in a slow release solid matrix such as a matrix of alginate, collagen, or a synthetic bioabsorbable polymer. Preferably, the wound dressing composition is sterile.
Preferably, the chronic wound is selected from the group consisting of venous ulcers, pressure sores, decubitis ulcers, diabetic ulcers and chronic ulcers of unknown etiology. Preferably, the chronic wound is not a periodontal disease condition.
It is to be understood that the term xe2x80x9calpha-1-antitrypsinxe2x80x9d as used herein encompasses all naturally occurring polymorphs of AAT. It also encompasses functional fragments of AAT, chimeric proteins comprising AAT or functional fragments thereof, homologs obtained by analogous substitution of one or more amino acids of AAT, and species homologs. Preferably, the AAT is a product of recombinant DNA technology, and more preferably the AAT is a product of transgenic technology. For example, the gene coding for AAT can be inserted into a mammalian gene encoding a milk whey protein in such a way that the DNA sequence is expressed in the mammary gland, as described in WO88/00239.
Without wishing to be bound by any theory, it is thought that the AAT improves the healing of chronic wounds by inhibiting human neutrophil elastase present in the wound. The healing of such wounds is determined by a complex balance between tissue formation and tissue destruction, and it appears that inhibition of neutrophil elastase by AAT shifts the balance in favour of wound healing.
In another aspect, the present invention provides a method for the treatment of chronic wounds as specified above, the method comprising administering a therapeutically effective amount of AAT to the patient. Preferably, the AAT is administered topically, more preferably in a topical composition as described above.